Bradykinin B1 and B2 receptors (B1R and B2R) are G protein-coupled receptors (GPCRs) and have long been known to have an important role in pain and inflammation pathways (Campos et al, TRENDS in Pharmacological Sciences 2006, 27:646-651; Calixto et al, British Journal of Pharmacology 2004, 143:803-818). The peptides, bradykinin (BK; Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg [SEQ ID NO:5]) and kallidin (Lys-BK; Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg [SEQ ID NO:6]), are produced by enzymatic cleavage of kininogens and act as the endogenous agonists for the constitutively expressed and widely distributed B2R (Leeb-Lundberg et al, Pharmacological Reviews 2005, 57:27-77). The removal of the C-terminal Arg from BK and kallidin by carboxypeptidase N generates [des-Arg9]BK and [des-Arg10]kallidin, respectively, which are the natural agonists for the inducible B1R (Leeb-Lundberg et al, ibid.).
B1R is known to be involved in various types of pain and inflammatory syndromes (Calixto et al, British Journal of Pharmacology, 2004, 143:803-818), cardiovascular inflammatory pathologies, such as endotoxic shock, atheromatous disease and myocardial ischemia (McLean et al, Cardiovascular Research, 2000, 48:194-210) and a variety of cancers (Molina et al. Breast Cancer Research and Treatment 2009, 118:499-510; Taub et al. Cancer Research 2003, 63:2037-2041; Chee et al. Biological Chemistry 2008, 389:1225-1233; Yang et al, Journal of Cellular Biochemistry 2010, 109:82-92; Raidoo et al, Immunopharmacology 1999, 43:255-263; and Wu et al, International Journal of Cancer 2002, 98:29-35).
Receptors can be useful targets for various in vivo imaging techniques (see, Mankoff et al., Journal of Nuclear Medicine, 2008, 49:149S-163S). Receptor imaging, however, presents certain challenges. For example, receptor imaging probes need to have high specific activity, so that these compounds can be used in low quantities to provide an imaging signal, in order to avoid saturating the receptors. Techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are, therefore, preferred for molecular imaging of receptors as these techniques employ radionuclides and can generate images using nano- to picomolar amounts of imaging probes. Even with techniques such as PET and SPECT, however, it is important that the imaging probe exhibits sufficiently low nonspecific binding to avoid interference with visualization at the target site(s), as well as clearance rates that are sufficiently slow to allow for uptake at the target site(s) but rapid enough to allow the uptake to be visualized without interference from unbound probe.
Radionuclides that can be used in SPECT typically have longer half-lives than those used in PET. Typical radionuclides for SPECT imaging include 123I, 99mTc, 67Ga, 111In, and 201Tl, whereas the primary radionuclides for PET imaging are 11C, 18F, 44Sc, 64Cu, and 68Ga. While 11C provides versatility with respect to the type of compound that may be labelled, its use in synthesis is limited due to the availability of only limited precursors and the short half-life (20.3 minutes) of this isotope, which requires its introduction as late as possible in the synthetic pathway as well as an on-site cyclotron to generate the isotope.